(12) United States Patent
`Buschmann et al.
`
`US006248737B1
`US 6,248,737 B1
`Jun. 19, 2001
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54) 1-PHENYL-3-DIMETHYLAMINOPROPANE
`COMPOUNDS WITH A
`PHARMACOLOGICAL EFFECTS
`
`(75) Inventors: Helmut Buschmann, Aachen;
`Wolfgang Strassburger, Wuerselen;
`Elrnar Friderichs, Stolberg, all of (DE)
`
`(73) Assignee: Gruenenthal GmbH, Aachen (DE)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 08/466,911
`(22) Filed:
`Jun. 6, 1995
`(30)
`Foreign Application Priority Data
`
`Jul. 23, 1994
`
`(DE) .............................................. .. 44 26 245
`
`(51) Int. Cl.7 ..................... .. A61K 31/135; C07C 217/62
`
`(52) US. Cl. ..................... .. 514/231.8; 514/114; 514/452;
`514/456; 514/488; 514/534; 514/546; 514/653;
`514/654; 544/86; 549/362; 549/398; 558/190;
`558/273; 560/32; 560/37; 560/66; 560/250;
`560/252
`(58) Field of Search ................................... .. 564/355, 356,
`564/374, 440, 442, 443; 514/653, 654,
`114, 231.8, 512, 546, 452, 456, 488, 534;
`544/86; 558/190, 273; 560/252, 32, 37,
`66, 250; 549/362, 398
`
`(56)
`
`References Cited
`
`US. PATENT DOCUMENTS
`
`4,285,961 * 8/1981 Prucher et al. ................ .. 424/273 R
`5,310,756 * 5/1994 Jakobsen et al.
`514/524
`5,811,582 * 9/1998 Buschmann et al. .............. .. 564/355
`5,981,599 * 11/1999 Moe etal. ......................... .. 514/654
`6,001,884 * 12/1999 Nemeth etal.
`514/699
`6,011,068 * 1/2000 Nemeth etal.
`514/654
`6,017,965 * 1/2000 Mueller et al.
`514/649
`6,022,894 * 2/2000 Del Mar etal. ..
`514/524
`6,031,003 * 2/2000 Nemeth etal. .................... .. 514/579
`6,052,610 * 4/2000 Mueller et al. .................... .. 514/628
`6,071,970 * 6/2000 Mueller et al. .................... .. 514/648
`
`FOREIGN PATENT DOCUMENTS
`
`1051281 * 2/1959
`2412798 * 9/1974
`124521
`3/1977
`3242922
`5/1984
`176049
`4/1986
`WO 95/21612 * 8/1995 (WO).
`
`OTHER PUBLICATIONS
`
`LagidZe et al., Chemical Abstracts, vol. 78, abstract 57901,
`1972.*
`Tramatoni, “Advances in the Chemistry of Mannich Bases”,
`Synthesis, 1973, pp. 703—775.
`J. Am. Chem. Soc., 74, p. 1316 (1952).
`Chem. Abstr, 63, p. 6912e (1965).
`
`Olofsson et al., “Value of the VinyloXycarbonyl Unit in
`HydroXyl Protection: Application of the Synthesis of Nalor
`phine”, Tetrahedron Letters, No. 18, 1977, pp. 1571—1574.
`
`Welch et al., “Reduction of Aryl Diethyl phosphates With
`Titanium Metal: A Method for DeoXygenation of Phenols”,
`J. Org. Chem., 43, pp. 4797—4799 (1978).
`Ditter et al., “Acetaminophen Prodrugs I”, J. Pharm. Sci.,
`57, pp. 774—780 (1968).
`
`Thorberg et al., “Carbamate Ester Derivatives as Potential
`Prodrugs of the presynaptic Dopamine Autoreceptor
`Agonist .
`.
`. ”, J. Med. Chem., 30, pp. 2008—2012 (1987).
`
`Bundgaard et al., “A Novel Solution—Stable, Water Soluble
`Prodrug Type for Drugs Containing A HydroXyl or an
`HG—Acidic Group”, J. Med. Chem., 32, pp. 2503—2507
`(1989).
`Raffa et al., “Opioid and Nonopioid Components Indepen
`dently Contribute to the Mechanism of the Action of Tra
`madol .
`.
`. ”, J. Pharmacol. Exptl. Ther, 260. pp. 275—285
`(1992).
`BurWell, “The Cleavage of Ethers”, Chem. Rev., 54, pp.
`615—685 (1954).
`Winterfeldt, “Applications of Diisobutylaluminium Hydride
`(DIBAH) and Triisobutylaluminium (TIBA) as Reducing
`Agents in Organic Synthesis”, Synthesis, 1975, pp. 617—630.
`Bundgaard, “Novel Chemical Approaches in Prodrug
`Design”, Drugs of the Future, 16, pp. 443—458, (1991).
`Organic Reactions, 35, Chapter 3, pp. 513—633 (1988).
`Goodman & Gilman, The Pharmacological Basis of T hera
`peutics, Pergamon Press, NeW York (1990).
`
`Potti et al., “Use of 3—AZabicyclo [3,2,1]octane in the
`Mannich Reaction”, J. Pharm. Sci., 57, pp. 1487—1493—
`(1968).
`
`(List continued on neXt page.)
`
`Primary Examiner—Richard L. Raymond
`(74) Attorney, Agent, or Firm—CroWell & Moring, L.L.P.
`(57)
`ABSTRACT
`1-phenyl-3 -dimethylaminopropane compounds correspond
`ing to the formula I
`
`a method of preparing them, and the use of these substances as analgesic
`active ingredients in pharmaceutical compositions.
`
`8 Claims, No Drawings
`
`RS 1017 - 000001
`
`

`
`US 6,248,737 B1
`Page 2
`
`OTHER PUBLICATIONS
`
`a1., “Stereochemistry of Disasteromeric
`Spassov et
`3—Dia1ky1aminopropano1s and O—Derivatives”, J. Prakt.
`Chem, 323, pp. 793—800 (1981).
`Parimmo et a1., “New Compounds: Some Potential Chemo
`therapeutic Agents Derived from Ara1ky1 Ketones”, J.
`Pharm. Sci, 59, pp. 1038—1041 (1970).
`
`Raffa et a1., “Complementary and Synergistic Antinoncice
`ptive Interaction betWeen the Enantiomers of Tramado1”, J.
`Pharmacol. Exptl. T her, 267, pp. 331—340 (1993).
`
`Chem. Abstn, 54, 2093c (1960).
`
`* cited by examiner
`
`RS 1017 - 000002
`
`

`
`US 6,248,737 B1
`
`1
`1—PHENYL-3—DIMETHYLAMINOPROPANE
`COMPOUNDS WITH A
`PHARMACOLOGICAL EFFECTS
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to 1-phenyl-3
`dimethylaminopropane compounds, to a method of prepar
`ing them, and to the use of these substances as pharmaceu
`tical active ingredients.
`The treatment of chronic and non-chronic pain situations
`is of great importance in medicine. This is re?ected in the
`large number of publications. Thus, for example,
`1-naphthyl-3-aminopropane-1-ols With an analgesic
`narcotic effect are knoWn from EP 176 049. Secondary and
`tertiary alcohols With y-amino groups are described in J.
`Pharm. Sci. 59, 1038 (1970) and in]. Prakt. Chem. 323, 793
`(1981); phenyl-dimethylaminopropanols containing a para
`substituted phenyl radical are described in Chem. Abstr. 54,
`20963c (1960) and in Chem. Abstr'. 63, 6912e (1965). These
`compounds also possess analgesic properties. In contrast,
`the 3-dimethylaminopropan-1-ols containing 2-phenyl radi
`cals described in DE 32 42 922 have an antidepressant
`effect. The 1-phenyl-propan-1-ols described in J. Pharm.
`Sci. 57, 1487 (1968) have different pharmacological effects
`depending on the y-aZa ring.
`Opioids have been used for many years as analgesics for
`the treatment of pain, although they give rise to a series of
`side effects, for eXample addiction and dependency, respi
`ratory depression, gastrointestinal inhibition and obstipa
`tion. They can therefore only be given over an eXtended
`period of time or in higher doses subject to special precau
`tionary measures such as special prescription regulations
`(Goodman, Gilman in “The Pharmacological Basis of
`Therapeutics”, Pergamon Press, NeW York (1990)).
`Tramadol hydrochloride—(1RS,2RS)-2
`[(dimethylamino)methyl]- 1 -(3-methoXyphenyl)
`cycloheXanol hydrochloride—assumes a special position
`amongst centrally-acting analgesics, since this active ingre
`dient gives rise to a pronounced inhibition of pain Without
`the side effects Which are knoWn for opioids (J. Pharmacol.
`Exptl. Ther.4 267, 331 (1993)). Tramadol is a racemate and
`consists of identical amounts of (+) and (—) enantiomer. In
`vivo the active ingredient forms the metabolite
`O-desmethyl-tramadol, Which is likeWise present as a miX
`ture of enantiomers. Investigations have shoWn that both the
`enantiomers of tramadol and the enantiomers of tramadol
`metabolites contribute to the analgesic effect (J. Pharmacol.
`Exp. Ther. 260, 275 (1992)).
`
`SUMMARY OF THE INVENTION
`
`The underlying object of the present invention Was to
`provide substances With an analgesic effect, Which are
`suitable for the treatment of severe pain Without giving rise
`to the side effects Which are typical of opioids.
`A further object Was to provide analgesic substances
`Which do not exhibit the side effects, for eXample nausea and
`vomiting, Which occur during treatment With tramadol in
`some cases.
`It has been found that these stringent requirements are
`ful?lled by certain 1-phenyl-3-dimethylaminopropane com
`pounds. These substances are characteriZed by a pronounced
`analgesic effect Which is signi?cantly enhanced compared
`With that of tramadol.
`The present invention accordingly relates to 1-phenyl-3
`dimethylaminopropane compounds of formula I
`
`10
`
`20
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`X R1
`
`R5_I \
`| k/ /
`
`R4
`
`R2
`R3
`/
`N
`
`in Which
`
`X represents OH, F, Cl, H or an OCOR6 group in Which R6
`is a C1_3-alkyl group;
`R1 is a C1_4-alkyl group;
`R2 represents H or a C1_4-alkyl group and R3 represents H
`or a straight chain C1_4-alkyl group, or R2 and R3 together
`constitute a C4_7 cycloalkyl radical, and
`if R5 is H, R4 represents meta-O-Z, Where Z is H, C1_4-alkyl,
`PO(OC1_4-alkyl)2, CO(OC1_5-alkyl), CONH—C6H4—
`(C1_3-alkyl) or CO—C6H4—R7, Wherein R7 is ortho
`OCOC1_3-alkyl or meta- or para-CH2N(R8)2, Where R8 is
`C1_4-alkyl or 4-morpholino, or R4 represents
`meta-S-C1_3-alkyl, meta-Cl, meta-F or meta-CR9R1OR11,
`ortho-OH, ortho-O-C2_3-alkyl, para-F or para
`CR9R1OR11, Where R9, R10 and R11 represent H or F, or
`if R5 represents Cl, F, OH or O—C1_3-alkyl in the para
`position, R4 represents Cl, F, OH or O—C1_3-alkyl in the
`meta-position, or
`R4 and R5 together represent 3,4-OCH=CH— or 3,4
`OCH=CHO—, as diastereoisomers or enantiomers in the
`form of free bases or salts of physiologically acceptable
`acids.
`1-phenyl-3-dimethylaminopropane compounds of for
`mula I are preferred in Which X constitutes OH, F, Cl or H;
`R1 represents a C1_4-alkyl group; R2 represents H or CH3,
`and R3 represents H or CH3, and if R5 is H, R4 represents
`
`or —CF3 in the meta-position, or para-CF3, or if R5 is a
`para-Cl or para-F, R4 represents meta-Cl or meta-F, or R4
`and R5 together represent 3,4-OCH=CH—.
`1-phenyl-3-dimethylaminopropane compounds of for
`mula I are particularly preferred in Which the R2 and R3
`radicals have different meanings, in the form of their dias
`tereoisomers of con?guration Ia
`
`R5
`44 R4
`
`The present invention also relates to a method of prepar
`ing 1-phenyl-3-dimethylaminopropane compounds of for
`mula I, in Which the variable X represents OH, Which is
`characteriZed in that a [3-dimethylaminoketone of formula II
`
`RS 1017 - 000003
`
`

`
`R1
`
`US
`6,248,737 B1
`
`v
`
`4
`
`0
`
`\
`R5—: k/ /
`
`R4
`
`1;
`N/
`
`is reacted With an organometallic compound of formula III
`
`in Which Z represents MgCl, MgBr, MgI or Li, to form a
`compound of formula I in Which X represents OH.
`The reaction of a [3-dimethylaminoketone With a Grignard
`reagent of formula III, in Which Z represents MgCl, MgBr
`or MgI, or With an organolithium compound of formula III,
`can be carried out in an a liphatic ether, for eXample diethyl
`ether and/or tetrahydrofuran, at temperatures betWeen —70°
`C. and +60° C. Organolithium compounds of formula II can
`be obtained by the replacement of halogen by lithium, for
`eXample, by reacting a compound of formula III, in Which Z
`represents Cl, Br or I, With a solution of n-butyllithium in
`n-heXane. [3-dimethylaminoketones of formula II can be
`obtained from ketones of general formula IV
`
`0
`
`by reaction With dimethylamine hydrochloride and formal
`dehyde in glacial acetic acid or in a C1_4-alkyl alcohol or by
`reaction With dimethylammonium ethylene chloride in
`acetonitrile using acetyl chloride as a catalyst (Synthesis
`1973, 703).
`Upon reaction of a [3-dimethylaminoketone of formula II,
`in Which the variables R2 and R3 have different meanings,
`With an organometallic compound of formula III, 1-phenyl
`3-dimethylaminopropane compounds of formula I are
`obtained having the relative con?guration of formula Ia
`
`10
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`15
`
`25
`
`35
`
`45
`
`55
`
`in Which the X and the dimethylamino group are disposed
`threo in relation to each other. In contrast, if the reaction for
`the preparation of 1-phenyl-1-hydroXy-3-aminopropanes
`Were carried out according to the method disclosed in DD
`124 521, ie if [3-aminoketones corresponding to the formula
`
`65
`
`Were reacted With an alkyl Grignard reagent RlMgHal, this
`Would result in compounds With the relative con?guration Ib
`
`in Which the OH group and the dimethylamino radical are
`disposed erythro in relation to each other.
`1-phenyl-3-dimethylaminopropane compounds of for
`mula I, in Which R4 and/or R5 constitute the OH group, can
`be prepared from the corresponding 1-(4(5)
`methoXyphenyl)-3-dimethylaminopropanol compounds by
`selective ether cleavage With diisobutylaluminium hydride
`in an aromatic hydrocarbon, for example toluene, at a
`temperature betWeen 60 and 130° C. (Synthesis 1975, 617).
`The present invention also relates to a method of prepar
`ing 1-phenyl-3-dimethylaminopropane compounds of for
`mula I, in Which X represents H, Which is characteriZed in
`that a compound of formula I, in Which X represents Cl, is
`reacted With Zinc borohydride, Zinc cyanoborohydride and/
`or tin cyanoborohydride.
`The reaction is usually conducted in a solvent, for
`eXample diethyl ether and/or tetrahydrofuran, at a tempera
`ture betWeen 0° C. and 30° C.
`Compounds of formula I, in Which X is H and R4 and/or
`R5 constitute the OH group, can be prepared from the
`corresponding methoXyphenyl compounds by heating them
`for several hours With concentrated hydrobromic acid
`(Chem. Rev. 54, 615 (1954); J. Am. Chem. Soc. 74, 1316
`(1952)).
`The present invention further relates to a method of
`preparing 1-phenyl-3-dimethylaminopropane compounds of
`formula I, Where X represents F, Which is characteriZed in
`that a compound of formula I, in Which X represents OH, is
`reacted With dimethylaminosulfur tri?uoride in a solvent.
`Suitable solvents include dichloromethane, 1,1,2
`trichloroethane and/or toluene. The reaction is usually con
`ducted at a temperature betWeen —50° C. and +30° C. (Org.
`React. 35, 513 (1988)). If a compound of formula I With
`X=OH is used in Which R4 and/or R5 constitute OH groups,
`these OH groups must be protected before reaction With the
`?uorine compound, for eXample by reaction With benZoyl
`chloride.
`The present invention also relates to a method of prepar
`ing 1-phenyl-3-dimethylaminopropane compounds of for
`mula I, in Which X represents Cl, Which is characteriZed in
`that a compound of formula I, in Which X represents OH, is
`reacted With thionyl chloride.
`
`RS 1017 - 000004
`
`

`
`US 6,248,737 B1
`
`5
`The reaction is usually conducted in the absence of
`solvent at a temperature betWeen 0° C. and 20° C. Replace
`ment of OH by Cl is effected While maintaining the con
`?guration.
`The present invention also relates to a method of prepar
`ing 1-phenyl-3-dimethylaminopropane compounds of for
`mula I, in Which X represents an OCOR6 group Where R6 is
`a C1_3-alkyl, Which is characterized in that a compound of
`formula I, in Which X represents OH, is reacted With an acid
`chloride Cl—COOR6.
`The reaction is preferably conducted in a solvent, for
`example dichloromethane, toluene and/or tetrahydrofuran,
`at a temperature betWeen —10° C. and +30° C.
`1-phenyl-3-dimethylaminopropane compounds of for
`mula I, in Which R5 is H and R4 is a meta-phosphate group,
`meta-carbonate group, meta-carbamate group or meta
`carboxylate group, can be obtained by the reaction of the
`corresponding
`1-(3-hydroxyphenyl)-3
`dimethylaminopropane compounds of formula I in the form
`of their alkali salts With an alkali salt of a dialkyl
`chlorophosphate, With an alkyl chloroformate, With an aryl
`isocyanate or With a carboxylic acid chloride. These reac
`tions are usually conducted in a solvent, for example
`toluene, dichloromethane, diethyl ether and/or
`tetrahydrofuran, at temperatures betWeen —15° C. and +110°
`C. (Drugs of the Future 16, 443 (1991); J. Med. Chem. 30,
`2008 (1987) and 32, 2503 (1989); J. Org. Chem. 43, 4797
`(1978); Tetrahedron Lett. 1977, 1571;]. Pharm. Sci. 57, 774
`(1968)).
`The compounds of formula I can be converted in a knoWn
`manner into their salts With physiologically acceptable
`acids, for example hydrochloric acid, hydrobromic acid,
`sulfuric acid, methanesulfonic acid, formic acid, acetic acid,
`oxalic acid, succinic acid, tartaric acid, mandelic acid,
`fumaric acid, lactic acid, citric acid, glutamic acid and/or
`aspartic acid. Salt formation is preferably effected in a
`solvent, for example diethyl ether, diisopropyl ether, alkyl
`acetates, acetone and/or 2-butanone. Moreover, trimethyl
`chlorosilane in aqueous solution is suitable for the prepara
`tion of hydrochlorides.
`1-phenyl-3-dimethylaminopropane compounds of for
`mula I are toxicologically harmless, so that they are suitable
`as pharmaceutical active ingredients in drugs.
`Accordingly, the present invention also relates to the use
`of a 1-phenyl-3-dimethylaminopropane compound of for
`mula I as a pharmaceutical active ingredient. Compounds of
`formula I are preferably used for the treatment of pain.
`In addition to at least one 1-phenyl-3
`dimethylaminopropane compound of formula I, the analge
`sics according to the invention may contain carriers, ?llers,
`solvents, diluents, colorants and/or binders. The selection of
`auxiliary substances and of the amounts of the same to be
`used depends on Whether the drug is to be administered
`orally, intravenously, intraperitoneally, intradermally,
`intramuscularly, intranasally or locally, for example for
`infections of the skin, of the mucous membranes or of the
`eye. Preparations in the form of tablets, dragees, capsules,
`granules, drops, liquids and syrups are suitable for oral
`application. Solutions, suspensions, readily reconstitutable
`dry preparations, and sprays are suitable for parenteral,
`topical and inhalative applications. Compounds of formula
`I according to the invention in a deposit in dissolved form or
`in a patch, optionally With the addition of a skin penetration
`promoter, are suitable preparations for percutaneous appli
`cation. Forms of preparations Which can be administered
`orally or percutaneously may effect delayed release of the
`compounds of formula I according to the invention.
`
`10
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`15
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`20
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`25
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`30
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`35
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`40
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`50
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`55
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`60
`
`65
`
`6
`The amount of active ingredient to be administered to
`patients varies depending on the patient’s Weight, on the
`manner of administration, the indication and the degree of
`severity of the illness. 50 to 500 mg/kg of at least one
`1-phenyl-3-dimethylaminopropane compound of formula I
`are usually administered.
`
`EXAMPLES
`
`The yields of the compounds prepared have not been
`optimised.
`All temperatures are uncorrected.
`Unless otherWise indicated, petroleum ether With a boil
`ing point of 50—70° C. Was used. The term “ether” denotes
`diethyl ether.
`Silica gel 60 (0.040—0.063 mm) manufactured by E.
`Merck, Darmstadt, Was used as the stationary phase for
`column chromatography.
`Thin layer chromatography investigations Were con
`ducted using prefabricated silica gel 60 F 254 HPTLC plates
`manufactured by E. Merck, Darmstadt.
`Racemate separation Was effected on a Chiracel OD
`column.
`The mixture ratios of the mobile phases for all chromato
`graphic investigations are expressed as volume/volume.
`RT denotes room temperature; m.p. denotes melting
`point.
`
`Example 1
`
`(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2
`methylpentan-3-ol Hydrochloride(1)
`207.63 g (1.11 mole) 3-bromoanisole dissolved in 400 ml
`dry tetrahydrofuran Were added drop-Wise to 26.99 g (1.11
`mole) magnesium turnings in 150 ml dry tetrahydrofuran so
`that the reaction mixture boiled gently. After the addition of
`3-bromoanisole Was complete the mixture Was heated under
`re?ux for one hour and thereafter Was cooled to 5—10° C.
`128.30 g (0.89 mole) 1-dimethylamino-2-methylpentan-3
`one dissolved in 400 ml tetrahydrofuran Were added at this
`temperature. The reaction mixture Was alloWed to stand
`overnight and then cooled again to 5—10° C. The Grignard
`solution Was decomposed by the addition of 300 ml of 20%
`ammonium chloride solution. The reaction mixture Was
`diluted With 400 ml ether, the organic phase Was separated
`off and the aqueous phase Was extracted tWice With 250 ml
`ether. The combined organic phases Were dried over sodium
`sulphate. After removing the solvent by distillation, the
`residue (212 g) Was taken up in 3200 ml 2-butanone and
`added to 120.60 g (1.11 mole) trimethylchlorosilane and 20
`ml Water. 121.5 g of hydrochloride (1) (38% theoretical)
`With a melting point of 198—199° C. crystallised out at 4—5°
`C.
`
`RS 1017 - 000005
`
`

`
`7
`Example 2
`
`US 6,248,737 B1
`
`8
`methanol. 14.9 g of base Were obtained, from Which 11.2 g
`of hydrochloride (2) (31% theoretical) With a melting point
`of 183—184° C. Were obtained With trimethylchlorosilane/
`Water in 2-butanone/diisopropyl ether.
`
`(+1)
`
`Example 4
`
`10
`
`(-1)
`
`15
`
`Enantiomers of (1):
`(—)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2
`methylpentan-3-ol Hydrochloride(—1)
`and
`(+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2
`methylpentan-3-ol Hydrochloride(+1).
`The base Was released from (1) With dichloromethane/
`sodium hydroxide solution. After drying the solution dichlo
`romethane Was distilled off under vacuum. The racemate
`Was then separated on the chiral HPLC column. The
`hydrochlorides, Which had a melting point of 150—151° C.,
`Were prepared from the enantiomers obtained by reaction
`With trimethylchlorosilane/Water in 2-butanone.
`(—1):
`yield: 42% theoretical
`[a1DRr=—31.8° (c=0.99; methanol)
`(+1):
`yield: 41% theoretical
`[a1DRr=+33.0° (c=0.96; methanol)
`Example 3
`
`20
`
`25
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`30
`
`40
`
`45
`
`50
`
`(2RS,3RS)-3-(3-isopropoxyphenyl)-1-dimethylamino-2
`methylpentan-3-ol Hydrochloride (3)
`
`25 g of crude mixture Were prepared analogously to
`Example 1 from 14.3 g (100 mmole) 1-dimethylamino-2
`methylpentan-3-one, 20.0 g (157 mmole) 1-bromo-3
`isopropoxybenZene and 2.79 g (115 mmole) magnesium
`turnings. This mixture Was introduced on to a 7x40 cm
`column packed With silica gel and eluted With 15:1 ethyl
`acetate/methanol. 9.0 g of base Were obtained, from Which
`8.3 g of hydrochloride (3) (26% theoretical) With a melting
`point of 133—134° C. Were obtained With
`trimethylchlorosilane/Water in 2-butanone.
`
`Example 5
`
`55
`
`(2RS,3RS)-3-(3-chlorophenyl)-1-dimethylamino-2
`methylpentan-3-ol Hydrochloride (4)
`
`(2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2
`methylpentan-3-ol Hydrochloride (2)
`39 g of crude mixture Were prepared analogously to
`Example 1 from 15 g (105 mmole) 1-dimethylamino-2
`methylpentan-3-one, 35.5 g (157 mmole) 4-bromo-1,2
`dichlorobenZene and 3.8 g (157 mmole) magnesium turn
`ings. This mixture Was introduced on to a 7x40 cm column
`packed With silica gel and eluted With 4:1 ethyl acetate/
`
`60
`
`65
`
`63 g of crude mixture Were obtained under the conditions
`cited for Example 1 from 38.0 g (270 mmole)
`1-dimethylamino-2-methylpentan-3-one, 74.7 g (390
`mmole) 1 -bromo-3-chlorobenZene and 9.50 g (390 mmole)
`magnesium turnings. This mixture Was introduced on to a
`7x45 cm column packed With silica gel and eluted With 7:1
`diisopropyl ether/methanol. 12.8 g of base Were obtained,
`from Which 10.8 g of hydrochloride (4) (14% theoretical)
`With a melting point of 160—162° C. Were obtained With
`trimethylchlorosilane/Water in 2-butanone/ether.
`
`RS 1017 - 000006
`
`

`
`US 6,248,737 B1
`
`10
`(2RS, 3R5)-1-dimethylamino-3-(3-?uorophenyl)-2
`methylpentan-3-ol Hydrochloride (7)
`
`70 g of crude mixture Were obtained under the conditions
`cited for Example 1 from 54.0 g (380 mmole)
`1-dimethylamino-2-methylpentan-3-one, 82.5 g (470
`mmole) 1-bromo-3-?uorobenZene and 9.23 g (470 mmole)
`magnesium turnings. This mixture Was introduced on to a
`7x50 cm column packed With silica gel and eluted With 1:1
`ethyl acetate/methanol. 13.0 g of base Were obtained, from
`Which 11.2 g of hydrochloride (7) (11.5% theoretical) With
`a melting point of 145—146° C. Was obtained With
`trimethylchlorosilane/Water in 2-butanone.
`
`Example 9
`
`9
`Example 6
`
`(2RS,3RS)-1-dimethylamino-2-methyl-3-(3
`tri?uoromethylphenyl)-pentan-3-ol Hydrochloride(5)
`21.2 g of crude mixture Were obtained under the condi
`tions cited for Example 1 from 14.3 g (100 mmole)
`1-dimethylamino-2-methylpentan-3-one, 29.3 g (130
`mmole) 1-bromo—3-tri?uoromethylbenzene and 3.2 g (130
`mmole) magnesium turnings. This mixture Was introduced
`on to a 6x40 cm column packed With silica gel and eluted
`With 10:1 diisopropyl ether/methanol. 9.1 g of base Were
`obtained, from Which 7.8 g of hydrochloride (5) (18.5%
`theoretical) With a melting point of 189—190° C. Was
`obtained With trimethylchlorosilane/Water in 2-butanone.
`
`Example 7
`
`10
`
`15
`
`20
`
`25
`
`30
`
`(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-m-tolyl)
`pentan-3-ol Hydrochloride (6)
`75 g of crude mixture Were obtained as in Example 1 from
`47.3 g (330 mmole) 1-dimethylamino-2-methylpentan-3
`one, 64.6 g (400 mmole) 3-bromotoluene and 9.72 g (400
`mmole) of magnesium turnings. This mixture Was intro
`duced on to a 7x50 cm column packed With silica gel and
`eluted With 7:1 diisopropyl ether/methanol. 24.3 g of base
`Were obtained, from Which 21.5 g of hydrochloride (6) (24%
`theoretical) With a melting point of 154—155° C. Were
`obtained With trimethylchlorosilane/Water in 2-butanone.
`
`Example 8
`
`35
`
`(2RS,3RS)-3-(3 -di?uoromethylphenyl)- 1 -dimethylamino -
`2-methylpentan-3-ol Hydrochloride(8)
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`7.0 g (34 mmole) 1-bromo—3-di?uoromethylbenzene, pre
`pared from 3-bromobenZaldehyde and diethylaminosulphur
`tri?uoride in dichloromethane according to Org. React. 35,
`513 (1988) Were dissolved in 110 ml of dry tetrahydrofuran
`and cooled to —75° C. After the addition of 21.12 ml (34
`mmole) of a 1.6 molar solution of n-butyllithium in hexane
`the mixture Was stirred for one hour at —75° C. 4.8 g (34
`mmole) 1-dimethylamino-2-methylpentan-3-one dissolved
`in 15 ml of dry tetrahydrofuran Were then added dropWise.
`The reaction mixture Was Warmed to room temperature over
`2.5 hours.
`
`Work-up Was effected by the drop-Wise addition of 65 ml
`of 5% hydrochloric acid With cooling in an ice bath, so that
`the internal temperature did not exceed 15° C. After phase
`separation the organic phase Was extracted With 40 ml of 5%
`hydrochloric acid. The combined aqueous phases Were
`Washed tWice With 50 ml ether. In order to release the base,
`the mixture Was added to concentrated sodium hydroxide
`solution and extracted With dichloromethane. 7.8 g of crude
`product Were obtained in this manner and Was introduced on
`to a 7x40 cm column packed With silica gel. Elution With 1:1
`ethyl acetate/methanol gave 4.89 g of base, from Which 4.6
`g of hydrochloride (8) (44% theoretical) With a melting point
`of 194—195° C. Was obtained With trimethylchlorosilane/
`Water in 2-butanone.
`
`RS 1017 - 000007
`
`

`
`US
`6,248,737 B1
`
`11
`Example 10
`
`12
`Example 12
`
`CF3
`
`(2RS,3RS)-1-dimethylamino-2-methyl-3-(3
`methylsulphanylphenyl)-pentan-3-ol Hydrochloride(9)
`38 g of crude mixture Were obtained under the conditions
`cited for Example 1 from 17.6 g (123 mmole)
`1-dimethylamino-2-methylpentan-3-one, 25.0 g (123
`mmole) 1-bromo-3-methylsulphanylbenZene and 3.0 g (123
`mmole) magnesium turnings. This mixture Was introduced
`on to a 7x40 cm column packed With silica gel and eluted
`With 10:1 ethyl acetate/methanol. 8.35 g of base Were
`obtained, from Which 7.2 g of hydrochloride (9) (19%
`theoretical) With a melting point of 159—160° C. Were
`obtained With trimethylchlorosilane/Water in 2-butanone.
`
`Example 11
`
`(2RS,3RS)-3-benZofuran-6-yl-1-dimethylamino-2
`methylpentan-3-ol Hydrochloride(10)
`3.45 g (18 mmole) 6-bromobenZofurane (prepared
`according to EP 355 827) and 6 ml 1,2-dibromoethane,
`dissolved in 60 ml dry ether, Were added drop-Wise over 1.5
`hours to 2.12 g (87 mmole) magnesium turnings in 30 ml dry
`ether; after the addition the mixture Was heated under re?ux
`for 30 minutes. Thereafter, 2.5 g (18 mmole)
`1-dimethylamino-2-methylpentan-3-one dissolved in 7.5 ml
`ether Was added drop-Wise over 1.5 hours Whilst cooling in
`an ice bath to maintain an internal temperature of 5—10° C.
`The reaction mixture Was alloWed to stand for 12 hours at
`room temperature, and Was then cooled again to 5—10° C.
`and added to 35 ml of 20% aqueous ammonium chloride
`solution. After phase separation, the aqueous phase Was
`extracted tWice With 50 ml ether. The combined organic
`phases Were dried over sodium sulphate. After removing the
`solvent by distillation the residue (3.9 g) Was introduced on
`to a 5x16 cm column packed With silica gel. 0.95 g of base
`Were obtained by elution With 7:1 diisopropyl ether/
`methanol, from Which 0.82 g of hydrochloride (10) (15.5%
`theoretical) With a melting point of 162° C. Were obtained
`With trimethylchlorosilane/Water in ethyl acetate/2
`butanone.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`H—Cl
`
`(2RS,3RS)- 1-dimethylamino-2-methyl-3-(4
`tri?uoromethylphenyl)-pentan-3-ol Hydrochloride (11)
`44 g of crude mixture Were obtained as in Example 1 from
`20 g (140 mmole) 1-dimethylamino-2-methylpentan-3-one,
`31.5 g (140 mmole) 1-bromo-4-tri?uoromethylbenZene,
`16.5 g (680 mmole) magnesium turnings and 47 ml 1,2
`dibromoethane. This mixture Was introduced on to a 7x50
`cm column packed With silica gel and eluted With 5:1 ethyl
`acetate/methanol. 16.4 g of base Were obtained, from Which
`12.3 g of hydrochloride (11) (27% theoretical) With a
`melting point of 170—171° C. Were obtained With
`trimethylchlorosilane/Water in 2-butanone.
`
`Example 13
`(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-hexan-3-ol
`Hydrochloride (12)
`18.5 g of crude mixture Were obtained as in Example 1
`from 10 g (70 mmole) 1-dimethylamino-hexan-3-one, 18.7
`g (100 mmole) 1-bromo-3-methoxybenZene and 2.3 g (100
`mmole) magnesium turnings. This mixture Was introduced
`on to a 6x50 cm column packed With silica gel and eluted
`With 1:1 ethyl acetate/methanol. 6.84 g of base Were
`obtained, from Which 6.15 g of hydrochloride (12) (32%
`theoretical) With a melting point of 179—180° C. Were
`obtained With trimethylchlorosilane/Water in 2-butanone.
`
`Example 14
`(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-heptan-3-ol
`Hydrochloride (13)
`17.3 g of crude mixture Were obtained as in Example 1
`from 10 g (64 mmole) 1-dimethylamino-heptan-3-one, 15.9
`g (157 mmole) 1-bromo-3-methoxybenZene and 2.06 g (85
`mmole) magnesium turnings. This mixture Was introduced
`on to a 6x40 cm column packed With silica gel and eluted
`With ethyl acetate. 5.4 g of base Were obtained, from Which
`4.1 g of hydrochloride (13) (21% theoretical) With a melting
`point of 150° C. Were obtained With trimethylchlorosilane/
`Water in 2-butanone.
`
`Example 15
`(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-4,4
`dimethylpentan-3-ol Hydrochloride(14)
`37 g of crude mixture Were obtained as in Example 1 from
`18.6 g (118 mmole) 1-dimethylamino-4,4-dimethylpentan
`3-one, 28.4 g (152 mmole) 1-bromo-3-methoxybenZene and
`3.7 g (152 mmole) magnesium turnings. This mixture Was
`introduced on to a 7x40 cm column packed With silica gel
`and eluted With 5:1 ethyl acetate/methanol. 2.2 g of base
`Were obtained, from Which 1.8 g of hydrochloride (14) (5%
`theoretical) With a melting point of 213° C. Were obtained
`With trimethylchlorosilane/Water in 2-butanone.
`
`RS 1017 - 000008
`
`

`
`13
`Example 16
`
`US 6,248,737 B1
`
`14
`
`(+15):
`yield: 41% theoretical
`m.p.: 118—119° C.
`[ot]DRr=+41.0° (c=1.01; methanol)
`
`Example 18
`
`(2RS,3RS)-3-(3-dimethylamino-1 -ethyl-1-hydroxy-2
`methylpropyl)-phenol Hydrochloride(16).
`
`The base Was released from compound (1), Which Was
`prepared as in Example 1, With dichloromethane/sodium
`hydroxide solution. After drying the solution, dichlo
`romethane Was removed by distillation. 4.3 g (17 mmole) of
`base Were dissolved in 25 ml dry toluene and sloWly added
`drop-Wise to 71 ml (85 mmole) of a 1.2 molar solution of
`diisobutylaluminium hydride in toluene. When the addition
`Was complete, the mixture Was heated for 8 hours under
`re?ux and then cooled to room temperature. The reaction
`mixture Was diluted With 25 ml toluene. 9.4 ml ethanol
`folloWed by 9.4 ml Water Were added drop-Wise Whilst
`cooling in an ice bath. After stirring for one hour Whilst
`cooling in the ice bath the reaction mixture Was freed from
`aluminium salts by ?ltration, and the residue Was Washed
`three times With 50 ml toluene in each case. Thereafter the
`combined organic phases Were dried and toluene Was
`removed by distillation. 3.95 g of hydrochloride (16) (85%
`theoretical) With a melting point of 213—214° C. Were
`obtained from the base With aqueous hydrochloric acid
`solution in acetone.
`
`Example 19
`
`(+16)
`
`(2RS,3RS)-4-dimethylamino-2-(3-methoxyphenyl)-3
`methylbutan-3-ol Hydrochloride(15)
`21 g of crude mixture Were obtained as in Example 1 from
`5.3 g (41 mmole) 4-dimethylamino-3-methylbutan-3-one,
`23.0 g (123 mmole) 1-bromo-3-methoxybenZene and 3.0 g
`(123 mmole) magnesium turnings. This mixture Was intro
`duced on to a 45x27 cm column packed With silica gel and
`elut